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Abstract

Background

Research into neural mechanisms of drug abuse risk has focused on the role of dysfunction
in neural circuits for reward. In contrast, few studies have examined the role of
dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically
regarded as a risk factor for mood and anxiety disorders, threat-related amygdala
reactivity may serve as a protective factor against substance use disorders, particularly
in individuals with exaggerated responsiveness to reward.

Findings

We used well-established neuroimaging paradigms to probe threat-related amygdala and
reward-related ventral striatum reactivity in a sample of 200 young adult students
from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking
were assessed using self-report. We found a significant three-way interaction between
threat-related amygdala reactivity, reward-related ventral striatum reactivity, and
recent stress, wherein individuals with higher reward-related ventral striatum reactivity
exhibit higher levels of problem drinking in the context of stress, but only if they
also have lower threat-related amygdala reactivity. This three-way interaction predicted
both contemporaneous problem drinking and problem drinking reported three-months later
in a subset of participants.

Conclusions

These findings suggest complex interactions between stress and neural responsiveness
to both threat and reward mediate problem drinking. Furthermore, they highlight a
novel protective role for threat-related amygdala reactivity against drug use in individuals
with high neural reactivity to reward.

Keywords:

Amygdala; Ventral striatum; Threat; Reward; Stress; Alcohol

Findings

Increased amygdala reactivity to threat has been consistently associated with heightened
risk for mood and anxiety disorders [1]. In contrast to this heightened risk, a few studies have suggested that threat-related
amygdala reactivity may buffer risk for drug abuse. Specifically, one study reported
that individuals at high familial risk for alcoholism exhibit relatively reduced threat-related
amygdala reactivity [2]. The authors speculate that this pattern may indicate reduced sensitivity to the
harmful consequences of excessive alcohol use in those at risk.

Consistent with these findings, a recent study has linked a genetic variant conferring
increased risk for drug abuse [3] with relatively decreased threat-related amygdala reactivity [4]. Interestingly, the same genetic risk variant was associated with heightened reward-related
reactivity of the ventral striatum (VS), a neural phenotype associated with both risk
for and pathophysiology of drug abuse [5,6]. These data suggest a potentially synergistic effect of threat-related amygdala reactivity
and reward-related VS reactivity in precipitating drug abuse risk. In addition to
variability in these neural phenotypes, drug abuse risk is moderated by environmental
factors, such as recent life stress [7]. Both VS and amygdala function are also affected by stress [8], suggesting that complex interactions between these neural circuits may contribute
to variability in stress-related risk for drug abuse.

Here, we explore the interactions of recent life stress, threat-related amygdala and
reward-related VS reactivity in predicting variability in self-reported problem drinking
in a sample of 200 young adults. We focused on drinking because alcohol is the most
commonly used and abused drug in adolescents and young adults [9], and its use is often triggered by stress [7]. Using two well-characterized BOLD fMRI paradigms ([10] Figure 1A-B), we quantified threat-related amygdala and reward-related VS reactivity. Recent
life stress and problem drinking were assessed using the Life Events Scale for Students
(LESS, [11]) and the Alcohol Use Disorder Identification Test (AUDIT, [12]), respectively. Based on prior research, we predicted that higher threat-related
amygdala reactivity would protect against increased problem drinking in the context
of stress, particularly in those whose risk is exaggerated by higher reward-related
VS reactivity.

As expected [7], there was a significant positive correlation between recent stress and problem drinking
(r=0.22, p=0.004). Critically, however, this relationship was moderated by amygdala
and VS reactivity (Figure 1A-B). Specifically, a three-way interaction predicting problem drinking emerged between
recent stress, left amygdala reactivity, and left VS reactivity (ΔR2=0.035, b=−0.26, p=0.012). Among participants with low VS reactivity (1 SD below mean;
Figure 1C), stress did not predict any increases in drinking, regardless of amygdala reactivity.
Among participants with high VS reactivity (1 SD above mean), who are likely to be
at increased risk for drug abuse [5], stress predicted increased problem drinking only for those who also had low amygdala
reactivity (1 SD below mean; Figure 1D). This three-way interaction remained significant after controlling for gender,
age, and race/ethnicity (ΔR2=0.031, b=−0.25, p=0.012). There was no such interaction for right VS or amygdala
reactivity (p values > 0.10), and no significant main effects of either amygdala or
VS reactivity on problem drinking (p values > 0.14).

Demonstrating the specificity of these findings to recent, as opposed to early, life
stress, the three-way interaction remained significant when total scores from the
Childhood Trauma Questionnaire [13] were added as an additional covariate (left VS: R2=0.033, b=−0.25, p=0.011). Furthermore, childhood trauma did not interact with amygdala
or VS reactivity to predict problem drinking (p values > 0.63). Finally, the same
three-way interaction emerged in a subsample of participants (N=85) who completed
a three-month follow-up assessment of stress and problem drinking (without covariates:
ΔR2=0.085, b=−0.365, p=0.008; with covariates: ΔR2=0.063, b=−0.324, p=0.019). The temporal stability of this interaction suggests that
stress-related problem drinking reflects rather than affects the relative neural responsiveness
to threat and reward.

An important caveat to consider when interpreting these findings is the possibility
that participants drinking more alcohol may experience more stressful life events
partially as a result of their increased drinking, rather than the other way around.
Since our measures of stress and problem drinking are based on retrospective self-report
spanning the past 12 months, the directionality of the association between stress
and drinking cannot be determined on the basis of these analyses. Thus we cannot rule
out the alternative interpretation that individuals with high VS reactivity and low
amygdala reactivity are more likely to experience highly impactful stressful life
events in the context of problem drinking. This interpretation would be consistent
with a heightened drive to pursue immediate rewards, coupled with a reduced ability
to recognize and avoid threat in those individuals.

Limitations notwithstanding, we provide novel evidence that recent life stress is
associated with increased problem drinking only in individuals with higher reward-related
VS reactivity and lower threat-related amygdala reactivity. Consistent with the relative
temporal stability of amygdala [14] and VS [15] reactivity, the interactions between these neural phenotypes and recent life stress
predicted future problem drinking in a subset of participants. This finding suggests
that the pattern we observe spans longer periods of time and may be useful in identifying
individuals at particularly high risk for developing alcohol and possibly other substance
use disorders in the wake of stress. Future research identifying factors that predict
the observed variability in neural responsiveness to threat and reward (e.g., functional
genetic polymorphisms) can inform the development of biomarkers for drug abuse risk
and interventions targeting these specific intermediate phenotypes.

Competing interests

Authors’ contributions

YSN and ARH designed this study. YSN conducted the statistical analyses and drafted
the manuscript. ARH edited the manuscript. Both authors read and approved the final
manuscript.

Acknowledgments

YSN is supported by a Howard Hughes Medical Institute International Student Research
fellowship. The Duke Neurogenetics study is supported by Duke University. We would
like to thank Annchen Knodt, Adam Gorka, Bart D. Brigidi, and Vanessa V. Sochat for
their assistance in data collection and pre-processing.